Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis

Ohshiba, Tomoyasu; Miyaura, Chisato; Ito, Akira

doi:10.1016/s0006-291x(02)02937-6

Cited by 58 publications

(35 citation statements)

References 22 publications

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“…The mechanisms of osteoclast activation and osteolysis are complex and involve several cell types [2,3,8,12,14,16,19,[22][23][24][25][26]301. Although metastatic tumor cells have the in vitro capability to destroy bone directly [ 101, the main mechanism of cancer-induced osteolysis consists of stimulation of osteoclast-mediated bone destruction [3,9,12,20,22,24,35].…”

Section: Discussionmentioning

confidence: 99%

“…Controversies remain in the role of candidate factors [3,13,23,24]. Factors indirectly induce synthesis of other local resorbing cytokines were PGE2, IL-1, TNF-a, (protein kinase A-mediated signal pathway) [2,3,12,13,19,24,25] and IL-6 (gp-130 mediated signal pathway) [ 14,23,28]. Identification of the molecular mechanisms responsible for osteolytic metastasis is crucial in designing effective therapy for this devastating complication.…”

Section: Introductionmentioning

confidence: 99%

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Bone resorption activity of osteolytic metastatic lung and breast cancers

Shih

Chen

2004

Journal of Orthopaedic Research

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Production of bone resorption mediators and bone resorption activity were compared among osteolytic metastatic cancers, normal bone tissues, and soft tissue metastatic cancers to search for the possible factors leading to cancer-induced bone resorption. Twenty-five patients with untreated osteolytic metastatic breast or non-small cell lung cancers consisted of the study group. Normal bone tissues obtained from the same patient were used as internal controls; and tumor tissues from patients with soft tissue metastasis were used as external controls. Serum and urinary bone turnover markers were measured. Tissues harvested during surgery were subjected to tissue culture. The levels of prostaglandin E2 ( PGE2), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) in the supernatant after 72 h of culture were measured. Bone resorption activity was measured by calcium release from cultured calvarias, and bone volume as well as osteoclast number in bone sections. Patients with osteolytic metastatic cancers showed significantly decreased serum osteocalcin, increased serum alkaline phosphatase, and urinary deoxypyridinoline levels. Osteolytic metastatic cancers produced significantly more PGE2 than both controls. Conditioned medium from osteolytic metastatic tumors showed significantly enhanced bone resorption activity, and indomethacin significantly reduced this activity. Levels of PGE?, and bone resorption activity increased in osteolytic tumor tissues than soft tissue metastatic tissues in the same patient indicated that the same tumor cells might respond differently to different microenvironments. Our observation showed that PGE2 was produced by osteolytic metastatic cancers and stimulated bone resorption in mice calvarias. PGEz inhibitor may be applicable in reducing bone resorption by osteolytic metastatic cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bone resorption activity of osteolytic metastatic lung and breast cancers

Shih

Chen

2004

Journal of Orthopaedic Research

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“…Furthermore, EP4 contributed to the stimulation of migration of colorectal (Sheng et al, 2001) and breast (Timoshenko et al, 2003) cancer cells. EP4 receptors were also responsible for an upregulation of iNOS gene expression under inducible conditions in murine breast cancer cells that increased their invasive capacity (Timoshenko et al, 2004), as well as in osteoclast development and bone metastasis in a breast cancer model (Ohshiba et al, 2003).…”

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confidence: 99%

COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer

et al. 2006

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Increased expression of COX-2 or VEGF-C has been correlated with progressive disease in certain cancers. Present study utilized several human breast cancer cell lines (MCF-7, T-47D, Hs578T and MDA-MB-231, varying in COX-2 expression) as well as 10 human breast cancer specimens to examine the roles of COX-2 and prostaglandin E (EP) receptors in VEGF-C expression or secretion, and the relationship of COX-2 or VEGF-C expression to lymphangiogenesis. We found a strong correlation between COX-2 mRNA expression and VEGF-C expression or secretion levels in breast cancer cell lines and VEGF-C expression in breast cancer tissues. Expression of LYVE-1, a selective marker for lymphatic endothelium, was also positively correlated with COX-2 or VEGF-C expression in breast cancer tissues. Inhibition of VEGF-C expression and secretion in the presence of COX-1/2 or COX-2 inhibitors or following downregulation of COX-2 with COX-2 siRNA established a stimulatory role COX-2 in VEGF-C synthesis by breast cancer cells. EP1 as well as EP4 receptor antagonists inhibited VEGF-C production indicating the roles of EP1 and EP4 in VEGF-C upregulation by endogenous PGE 2 . Finally, VEGF-C secretion by MDA-MB-231 cells was inhibited in the presence of kinase inhibitors for Her-2/neu, Src and p38 MAPK, indicating a requirement of these kinases for VEGF-C synthesis. These results, for the first time, demonstrate a regulatory role of COX-2 in VEGF-C synthesis (and thereby lymphangiogenesis) in human breast cancer, which is mediated at least in part by EP1/EP4 receptors.

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“…PGE 2 is one of the stimulators of osteoclastogenesis, with induction of RANKL in osteoblasts (17,18). Moreover, PGE 2 was reported to abolish apoptosis in some cancer cells by upregulating antiapoptotic proteins and enhancing cell survival pathways (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…PGE 2 mainly binds to EP4 in osteoblasts and activates cellular cAMP followed by upregulation of receptor activator of nuclear factor-nB ligand (RANKL; refs. 17,18). The increased RANKL consequently associates with RANK in monocytes/macrophages and enhances their differentiation into osteoclasts (19).…”

Section: Introductionmentioning

confidence: 99%

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

Takahashi

Uehara

Bando

et al. 2008

Molecular Cancer Therapeutics

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Prostaglandin E 2 (PGE 2 ) plays a key role in osteolytic bone metastasis as well as roles in inflammation, cell growth, and tumor development. PGE 2 exerts its effects by binding and activating E-prostanoid receptor (EP). In this study, we propose a new approach for blocking EP-mediated cell signaling using a soluble chimeric EP2 fragment. Mammalian expression vectors encoding several human EP2 cDNAs were introduced into 293 cells and the culture medium was tested for their function as a decoy receptor for PGE 2 . PGE 2 binding assays revealed that culture medium containing the second extracellular region of EP2 (FuEP2/Ex2) had binding activity. FuEP2/Ex2 neutralized PGE 2 -induced cyclic AMP production, cyclic AMP -responsive element binding protein phosphorylation, and subsequent induction of cyclooxygenase-2, interleukin (IL)-1B, and IL-6 mRNAs. In human osteoblasts, this culture medium neutralized the induction of receptor activator of nuclear factor-KB ligand mRNA. A stable transfectant expressing FuEP2/Ex2 was established from human prostate cancer PC-3 cells (PC3-FuEP2/Ex2). PC3-FuEP2/Ex2 cells grew at similar rates to vector control cells under normal culture conditions, although PGE 2 -induced growth stimulation was suppressed. Intraosseous injection of PC3-FuEP2/Ex2 cells into the tibia of athymic nude mice revealed that the degrees of tumor growth and osteolysis were decreased compared with control cellinjected mice, with decreased osteoclasts and increased apoptotic cells. Furthermore, the cyclooxygenase-2, IL-1B, and IL-6 mRNA levels were reduced in the tumor lesions. These data suggest that FuEP2/Ex2 is useful for treating osteolytic bone metastasis and cancers that depend on EP signaling for their growth and development.

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Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis

Cited by 58 publications

References 22 publications

Bone resorption activity of osteolytic metastatic lung and breast cancers

Bone resorption activity of osteolytic metastatic lung and breast cancers

COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

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